Excretion, Metabolism and Cytochrome P450 Inhibition of Methyl 3,4-Dihydroxybenzoate (MDHB): A Potential Candidate to Treat Neurodegenerative Diseases.

BACKGROUND AND OBJECTIVES: Methyl 3,4-dihydroxybenzoate (MDHB) has the potential to prevent neurodegenerative diseases (NDDs). The present work investigated its excretion, metabolism, and cytochrome P450-based drug-drug interactions (DDIs). METHODS: After intragastric administration of MDHB, the parent drug was assayed in the urine and faeces of mice. Metabolites of MDHB in the urine, faeces, brain, plasma and liver were detected by liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF/MS). A cocktail approach was used to evaluate the inhibition of cytochrome P450 isoforms by MDHB. RESULTS: The cumulative excretion permille of MDHB in the urine and faeces were found to be 0.67 ± 0.31 and 0.49 ± 0.44‰, respectively. A total of 96 metabolites of MDHB were identified, and all IC50 (half-maximal inhibitory concentration) values of MDHB towards cytochrome P450 isoforms were > 100 µM. CONCLUSIONS: The results suggest that MDHB has a low parent drug cumulative excretion percentage and that MDHB has multiple metabolites and is mainly metabolized through the loss of -CH2 and -CO2, the loss of -CH2O, ester bond hydrolysis, the loss of -O and -CO2, isomerization, methylation, sulfate conjugation, the loss of -CH2O and -O and glycine conjugation, glycine conjugation, the loss of two -O groups and alanine conjugation, the loss of -CH2O and -O and glucose conjugation, glucuronidation, glucose conjugation, etc., in vivo. Finally, MDHB has a low probability of cytochrome P450-based DDIs.

Evaluation of regional myocardial perfusion in methamphetamine abusers using real-time myocardial contrast echocardiography.

AIMS: To evaluate the feasibility of assessing regional myocardial perfusion using real-time myocardial contrast echocardiography (MCE) at rest for detecting coronary microcirculation abnormalities in methamphetamine abusers.Material and methods: Twenty-two male methamphetamine abusers (11 without chest pain, 11 with chest pain), free of ascertained coronary artery disease, were enrolled in this study. A control group of 22 age-matched male healthy participants was studied for comparison. Standard 2D, flow and tissue Doppler echo with measurements of cardiac morphologic and functional indicators,MCE with measurements of regional myocardial perfusion were performed, respectively. RESULTS: Compared to healthy participants, methamphetamine abusers had higher blood pressure, greater left ventricular mass index and more impaired diastolic function, with preserved cardiac sizes and systolic function. Methamphetamine abusers with chest pain had a faster heart rate than those without chest pain and healthy participants. MCE in methamphetamine abusers, especially with chest pain, had significant longer contrast agent arrival times, less functional capillary blood volumes, slower microvascular flow velocities and less myocardial perfusion than healthy participants (p<0.05). Moreover, along with the increases of dosage and duration of use (from group A to group C, group A: 1-2 g/day, <2 years; group B: 2-3 g/day, 2-5 years; group C: >3 g/day, >5 years) the reductions in the myocardial perfusion indices were more significant (p<0.01). The cutoff value with 5.1 dB2/s of the myocardial perfusion at the left ventricular apex had a sensitivity of 87.5%, specificity of 75.2% and accuracy of 81.9% for differentiating methamphetamine abusers from normal subjects. CONCLUSIONS: Real-time MCE can effectively detect coronary microcirculation abnormalities in methamphetamine abusers at rest and myocardial perfusion is significantly reduced in methamphetamine abusers. This finding may be involved in the occurrence and development of cardiac damage.

Methyl 3,4-Dihydroxybenzoate Induces Neural Stem Cells to Differentiate Into Cholinergic Neurons in vitro.

Neural stem cells (NSCs) have been shown as a potential source for replacing degenerated neurons in neurodegenerative diseases. However, the therapeutic potential of these cells is limited by the lack of effective methodologies for controlling their differentiation. Inducing endogenous pools of NSCs by small molecule can be considered as a potential approach of generating the desired cell types in large numbers. Here, we reported the characterization of a small molecule (Methyl 3,4-dihydroxybenzoate; MDHB) that selectively induces hippocampal NSCs to differentiate into cholinergic motor neurons which expressed synapsin 1 (SYN1) and postsynaptic density protein 95 (PSD-95). Studies on the mechanisms revealed that MDHB induced the hippocampal NSCs differentiation into cholinergic motor neurons by inhibiting AKT phosphorylation and activating autophosphorylation of GSK3ß at tyrosine 216. Furthermore, we found that MDHB enhanced ß-catenin degradation and abolished its entering into the nucleus. Collectively, this report provides the strong evidence that MDHB promotes NSCs differentiation into cholinergic motor neurons by enhancing gene Isl1 expression and inhibiting cell cycle progression. It may provide a basis for pharmacological effects of MDHB directed on NSCs.

Coronary sinus flow is reduced in methamphetamine abusers: a transthoracic echocardiographic study.

To compare the coronary sinus flow among healthy participants, methamphetamine abusers without chest pain and those with chest pain. One hundred and eight methamphetamine abusers: 53 ones without chest pain, 55 ones with chest pain, free of ascertained coronary artery disease, were enrolled in this study. A control group of 50 age-matched male healthy participants was studied for comparison. Standard 2D, flow and tissue Doppler echo with measurements of cardiac morphologic and functional indicators, coronary sinus flow, and inferior vena cava (IVC) ultrasound with measurements of the IVC dimensions and their collapsibility index were performed, respectively. Compared to healthy participants, methamphetamine abusers had higher blood pressure, greater left ventricular mass index and more impaired diastolic function, with preserved cardiac sizes, systolic function and right atrial pressure. Methamphetamine abusers with chest pain had faster heart rate than those without chest pain and healthy participants. Coronary sinus flow was significantly less in methamphetamine abusers than in healthy participants (P < 0.05), and was extremely lower in those with chest pain than in healthy participants (about one-fourth) (P < 0.01). The area under the curve (AUC) of coronary sinus flow was 0.913 (0.864-0.962), and the cutoff value with 221.65 mL/min had sensitivity of 83.4%, specificity of 87.2% and accuracy of 85.2% for differentiating methamphetamine abusers from healthy participants. While the AUC of coronary sinus flow was 0.996 (0.989-1.003), and the cutoff value with 172.59 mL/min had sensitivity of 100%, specificity of 93.3% and accuracy of 96.5% for predicting methamphetamine abusers with chest pain. Coronary sinus flow is significant reduced in methamphetamine abusers, which is maybe a good indicator for indentifying methamphetamine abusers from normal population, and for predicting methamphetamine abusers with chest pain.

Findings on 3D speckle tracking echocardiography in asymptomatic methamphetamine abusers.

To detect potential cardiac abnormalities in asymptomatic methamphetamine abusers using three-dimensional speckle tracking echocardiography (3D STE). Fifty-three male methamphetamine abusers, free of cardiac symptoms/signs, were enrolled in this study. A control group of 53 age-matched male normal subjects was studied for comparison. Standard 3D, flow and tissue Doppler echo with measurements of left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), ejection fraction (LVEF), the ratio of the early to late diastolic transmitral filling velocity (E/A), the ratio of the early diastolic transmitral filling velocity to the early diastolic septal tissue velocity (E/E') and 3D STE with measurements of global area strain (GAS), global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS) were performed, respectively. These echocardiographic parameters were compared between methamphetamine abusers and normal subjects, and receiver operating characteristic curve (ROC) analysis was done to differentiating methamphetamine abusers from normal subjects. LVESV, LVEDV, LVEF, E/A, E/E' ratios and GRS were not significantly different between methamphetamine abusers and normal subjects (p > 0.05). However, GAS, GLS and GCS were significantly less in methamphetamine abusers than in normal subjects (p < 0.05). The areas under ROC (AUC) for GAS were greatest among all the 3D STE derived LV global strains (GAS vs. GLS, GCS and GRS, 0.95 vs. 0.76, 0.69 and 0.61, respectively). The cutoff value with - 30.3% of GAS had sensitivity of 91.8%, specificity of 91.6% and accuracy of 91.3% for differentiating methamphetamine abusers from normal subjects. The potential myocardial function abnormalities can be detected by 3D STE in asymptomatic methamphetamine abusers, and GAS is a good indicator for indentifying methamphetamine abusers from normal population, which can be used to screening and monitor methamphetamine abuse, detect subclinical LV dysfunction, predict potential methamphetamine-related cardiotoxicity, and to initiate early cardioprotective therapy before the onset of overt heart failure in time.

Fetal regional myocardial strain rate in the membranous ventricular septum: changes with gestational age and the left ventricular mass and predictive value for a complete membranous ventricular septum (without defect).

To describe the fetal regional myocardial strain rate in the membranous ventricular septum across gestation and to determine their predictive value for a complete membranous ventricular septum (without defect) after delivery. In 1150 fetuses, the peak systolic strain rate (SRs), peak early diastolic strain rate (SRe) and peak late diastolic strain rate (SRa) in the membranous ventricular septum were measured at four time points across gestation (18-20, 24-26, 30-32 and 36-38 weeks). The integrity of the interventricular septum was examined at 12 weeks' postnatal age. The correlations between myocardial strain rates and gestational age as well as fetal left ventricular mass were analyzed, and the performance of myocardial strain rates in predicting a complete membranous ventricular septum was deducted. Strain rate absolute values in the membranous ventricular septum all increased across gestation. They all significantly correlated with gestational age and left ventricular mass. At 24 weeks during pregnancy, the areas under the receiver operating characteristics curve (AUC) for SRe and SRa were all > 0.72 (p < 0.05) in predicting a complete membranous ventricular septum, while the AUC for SRs was only 0.55. The sensitivity, specificity and accuracy of the cut off value (> 1.53 s-1) for SRe was 62.5, 85.7 and 73.3%, respectively, and the sensitivity, specificity and accuracy of the cut off value (> 1.51 s-1) for SRa was 75.2, 71.9 and 73.8%, respectively. The changes of myocardial strain rates in the membranous ventricular septum across gestation maybe can be used to predict a complete membranous ventricular septum after delivery.

The safety and feasibility of diagnostic acoustic radiation force impulse elastography used for eyes. A preliminary in vivo study.

AIMS: To assess the safety and feasibility of acoustic radiation force impulse (ARFI) elastography in the eyes of rats. Material and methods: One hundred and twenty-six SD rats were divided into 7 groups. Group 1 was the control group and Group 2 to Group 7 were investigated by ARFI elastography using increased powers of 5%, 10%, 20%, 50%, and 100% and repetitions of 5 or 10. The changes of ocular architecture structures and functions were examined by phthalmoscopic, histopathologic, and light reflex examination, and the expression level of IL-6, IL-8, and TNF-α was determined in days 1, 3, and 7 after ARFI elastography, respectively. RESULTS: A satisfactory ARFI elastography was obtained in all SD rats. The shear wave velocity (SWV) values of soft tissues behind the eyeball were significantly greater than those of the eyes (1.89±0.95 vs. 0.84±0.36 m/s, p<0.05). The SWV values of eyes and the soft tissues behind the eyeball did not differ among any groups at any time-point (p>0.05). The SD rats of each group showed good light perception, pupillary light reflex, and avoidance reaction induced by the sudden bright light from the dark environment at any time. In each group, ocular architecture structures were well preserved, and with a normal expression level of IL-6, IL-8, and TNF-α (p>0.05). CONCLUSIONS: Diagnostic ARFI elastography is a safe and feasible ultrasonic imaging mode and may potentially be applied for human eyes in its present form.

[The effects of 40 mg atorvastatin on serum lipids, inflammatory markers and clinical events in ACS patients post PCI].

OBJECTIVE: To assess the safety and effects of 40 mg atorvastatin on serum lipids, inflammatory markers and clinical events in ACS patients post PCI. METHODS: A total of 92 patients with ACS post successful PCI were randomly divided into atorvastatin 10 mg/d (group A) and atorvastatin 40 mg/d (group B) on top of the standard medical therapy. Blood were taken at baseline, 4, 12 and 24 weeks for serum alanine aminotransferase (ALT), lipids, high-sensitive C-reactive protein (hs-CRP) and matrix metalloprotease-9 (MMP-9) measurements. The major adverse cardiac events (MACE) were also observed. RESULTS: There was no significant difference in medication withdrawn (2 vs. 3 cases) due to increased ALT (3 times higher than normal) and incidence of MACE (5 vs. 7 cases) between the groups. TC and LDL were significantly reduced in both groups 4 weeks and thereafter post medication compared to pre-treatment (P < 0.05) and the reduction was more significant in group B than that in group A at 24 weeks post medication (P < 0.05) while TG and HDL remained unchanged. hs-CRP was significantly reduced at 12 and 24 weeks in both groups compared to baseline and the reduction was more significant in group B than that in group A at 24 weeks. MMP-9 was significantly reduced in both groups 4 weeks and thereafter post medication compared to pre-treatment (P < 0.05) and the reduction was more significant in group B than that in group A at 12 weeks post medication (P < 0.05). CONCLUSION: Both atorvastatin doses significantly reduced TC, LDL, hs-CRP and MMP-9 in ACS patients post PCI and the reduction was more significant in high dose atorvastatin group at 24 weeks while the MACE and drug withdraw rates were similar between the groups.